The present invention relates to novel compounds useful in the treatment and prophylaxis of degenerative bone disorders and to a method of their preparation. More specifically, the present invention contemplates novel compounds which are characterized by two active moieties. The first molecular domain possesses "bone-seeking" affinity while the second moiety is a specific inhibitor of the enzyme carbonic anhydrase and/or an inhibitor of bone resorption. The compounds of this invention can be administered alone or as pharmaceutically acceptable compositions and in convenient unit dosage form in a method for the treatment and prophylaxis of degenerative bone disorders.
Bone is a dynamic tissue, consisting of cells in a protein matrix, upon which is superimposed a crystalline structure of various calcium salts. Obviously, the bony skeleton serves as the rigid support for the body. In addition, bone is an organ which responds to hormones. In response to the parathyroid hormone (PTH), bone cells are able to solubilize the calcium salts in bone for use elsewhere in the body. This is a normal regulatory function of bone.
Diseases of excessive bone degeneration exist, including Paget's disease of bone and osteoporosis. The mechanisms are not well understood. In addition, the treatments available are, in general, ad hoc combinations of endocrine and mineral treatments which are often unsuccessful. Clinical osteoporosis is found in approximately 25% of post-menopausal women, and subclinical osteoporosis, which is responsible for untold numbers of bone fractures in elderly women, is far more widespread.
The mechanisms by which bone cells break down bone have been extensively studied but are not clearly defined. One likely scenario is that resorption is caused by the secretion, by bone cells, of acid and photeolytic enzymes. For these enzymes to have their effect, it is likely that the tissue must be decalcified first. Thus, the initiating step is thought to be the acidification of the internal environment of bone, which is responsible for decalcification. One such acid, which has been implicated for many years in these processes, is carbonic acid.
Assuming carbonic acid, which is generated by the enzyme carbonic anhydrase, is involved in bone resorption, then administration of a drug which inhibits carbonic anhydrase should inhibit the liberation of calcium from bone in response to PTH.
This is indeed the case, as was first demonstrated in mammals by Waite, et al. in the publication entitled, "Inhibition of Bone Resorption by Acetazolamide in the Rat", Endocrinology, 87: 1129(1970). One of the models used was the Induced Secondary Hyperparathyroid Rat (ISHR). ISHR were prepared by surgical ligation of the renal arteries. In the rat, the kidney is responsible for the metabolism of citrate. Upon ligation of the renal arteries, blood citrate concentration increases. Citrate chelates calcium and, while total calcium concentration is not affected by this binding, the amount of ionized calcium declines. This drop in plasma ionized calcium is the signal for the release of PTH. PTH, once released, signals bone to begin the resorptive process.
As one would predict, in the ISHR this increased release of PTH leads to an increase in total plasma calcium concentration. Administration of the carbonic anhydrase inhibitor acetazoramide to ISHR completely inhibits this response.
Using classic endocrine ablation/replacement studies, it has been shown that this effect is indeed due to a response to PTH. If the ISHR rat has the parathyroid glands removed, the expected increase in plasma calcium concentration is not observed. In this same animal (ISHR without parathyroids) however, administration of PTH evokes the response, while acetazoramide and other heterocyclic sulfonamides (carbonic anhydrase inhibitors) abolish it.
Later work in tissue culture showed that inhibition of PTH-induced resorption by acetazolamide is due to a direct interaction at the level of bone ("Carbonic Anhydrase and Bone Remodeling: Sulfonamide Inhibition of Bone Resorption in Organ Culture", Minkin and Jennings, Science, (June 1970)).
These studies would lead one to suggest that acetazolamide would be useful as an inhibitor of bone resorption. However, when one administers acetazolamide or other heterocyclic sulfonamide carbonic anhydrase inhibitors to normal animals, no change in plasma calcium concentration is observed. It has been demonstrated that the reason for this is that acetazolamide, while inhibiting calcium dissolution from bone due to the PTH response, also causes a systemic acidosis which of itself increases the shift of mineral from bone to blood. These two competing effects mask one another. (See, "Acidosis Inhibits the Hypocalcemic Effect of Acetazolamide", Lineberry and Waite, Pharmacol. Exp. Ther., 211: 452 (1979)).
Since these original studies several other factors relative to bone resorption have been determined. For example, the following have subsequently been observed: heterocyclic sulfonamides such as acetazolamide which inhibit carbonic anhydrase also inhibit bone resorption; these sulfonamides have both effects (carbonic anhydrase inhibition and inhibition of bone resorption) at the same concentrations; heterocyclic sulfonamides which do not inhibit carbonic anhydrase do not inhibit bone resorption; the sulfonamides also inhibit the bone resorptive effects of large doses of Vitamin D; and since other parameters of bone metabolism are not affected by the sulfonamides, this is not a simple toxicity to bone cells. These studies have been accomplished over a period of approximately 15 years and have involved both in vivo and in vitro work.
In view of these prior studies and other additional information recently derived herein, the compounds and methods of the present invention were contemplated in an effort to confer specificity on a novel inhibitor which would be localized specifically in bone so that it would have little or no effect on soft tissue carbonic anhydrase and would be available on site thereby overcoming the inadequacies which presently characterize known regiments for use of carbonic anhydrase inhibitors.